Tumors frequently re-activate genes whose expression is otherwise restricted to gametogenic tissues including the ovary, placenta and testes. Tumorigenic expression of these genes, known collectively as cancer-testes antigens (CTAs), has been documented for over 25 years; however functional knowledge of the contribution of these gene products to tumorigenesis remains scant. To examine the roles of CTAs in tumorigenic phenotypes, we have deployed a multidimensional quantitative discovery platform to examine the contribution of 120 CT antigens to neoplastic phenotypes and signaling cascades in 11 diverse tumorigenic settings. Using this screening platform, we have identified CT-antigens that are essential to many of the hallmarks of cancer including: 1) thwarting cell death signaling 2) enhanced energy production 3) hijacking developmental programs that promote self-renewal and metastases 4) adaption to low oxygen conditions inherent in the tumor microenvironment and 5) tolerance of DNA damage and aneuploidy. Thus, the objective of this proposal is to elaborate the contribution of cancer-testes antigens to neoplastic processes. The in-depth examination of the role of these CTA's in tumorigenic processes will provide conceptual breakthroughs with respect to the tumor cell regulatory environment as well as important new insights into tumor cell specific targets that could be exploited for therapeutic intervention.